It was initially found that pyridyl cyanoguanidines such as pinacidil (N-1,2,2-trimethylpropyl-N′-cyano-N″-(4-pyridyl)guanidine) are potassium-channel openers and therefore they were developed as antihypertensive agents. If the side chain of pinacidil was replaced with longer aryl group-containing side chain, it will lose its antihypertensive activity. However, in another aspect, it was found that the resulting compound has an antitumor activity when it is administered orally in a rat model with Yoshida ascitic tumor.
Various kinds of pyridyl cyanoguanidines with antiproliferative activities are disclosed in such as EP 660823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO 00/61559 and WO 00/61561, WO 98/54146, WO 2002/094813, U.S. Pat. No. 5,696,140. The structure-activity relation (SAR) of such compounds is discussed in C. Schou et al., Bioorganic and Medicinal Chemistry Letters 7 (24), 1997, 3095-3100, in which the antiproliferative effects of a large number of pyridyl cyanoguanidines on various human lung cancer and breast cancer cell lines as well as normal human fibroblasts have been tested in vitro. The compounds have been also tested in vivo by using nude mice with human lung cancer tumor xenograft. A specific compound (N-(6-(4-chlorophenoxy)hexyl)-N′-cyano-N″-(4-pyridyl)guanidine) with high antiproliferative activity in vitro and potent antitumor activity in the nude mice model was selected according to the SAR analysis.
Test results of further in vitro and in vivo tests of the compound N-(6-(4-chlorophenoxy)hexyl)-N′-cyano-N″-(4-pyridyl)guanidine are reported in P-J V Hjarnaa et al., Cancer Res. 59, 1999, 5751-5757. The compound exhibits an efficacy comparable to those of cytostatic agents daunorubicin and paclitaxel as control compounds in vitro, and also shows significantly lower antiproliferative activity against normal human endothelial cells. In the in vivo test carried out with nude mouse transplanted with human tumor cells, this compound shows highly potent antitumor activity and can also inhibit tumor cells which were resistant to conventional antitumor drugs such as paclitaxel.
It is well known that a crystalline form of a compound has a better stability than an amorphous form thereof, which can extend a shelf life of a drug substance, and is more suitable for preparing a formulation. As a result, a crystalline form, for example, a polymorph is a best choice of a physical form of a drug substance. However, no polymorph of N-(6-(4-chlorophenoxy)hexyl)-N′-cyano-N″-(4-pyridyl)guanidine (i.e. a compound of Formula (I)) is reported up to now.
